Inflammatory and metalloproteinases profiles predict three-month poor outcomes in ischemic stroke treated with thrombolysis

Gori, Anna Maria; Giusti, Betti; Piccardi, Benedetta; Nencini, Patrizia; Palumbo, Vanessa; Nesi, Mascia; Nucera, Antonia; Pracucci, Giovanni; Tonelli, Paolo; Innocenti, Eleonora; Sereni, Alice; Sticchi, Elena; Toni, Danilo; Bovi, Paolo; Guidotti, Mario; Tola, Maria Rosaria; Consoli, Domenico; Micieli, Giuseppe; Tassi, Rossana; Orlandi, Giovanni; Sessa, Maria; Perini, Francesco; DeLodovici, Maria Luisa; Zedde, Marialuisa; Massaro, Francesca; Abbate, Rosanna; Inzitari, Domenico

doi:10.1177/0271678x17695572

Cited by 38 publications

(43 citation statements)

References 33 publications

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“…Nezu et al [13] identified alpha-2-macroglobulin as an acute IS biomarker, and Gori et al [22] found that this protein was significantly associated with poor outcome (death within three months), suggesting that it contributes to cerebral damage after IS and thrombolysis. The authors conclude that high levels of alpha-2-macroglobulin may be a useful prognostic biomarker to identify patients with an increased probability of death after the administration of tissue plasminogen activator [22].…”

Section: Discussionmentioning

confidence: 99%

Distinct proteomic profiles in monozygotic twins discordant for ischaemic stroke

et al. 2019

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Background and Purpose: Stroke is a common disorder with significant morbidity and mortality, and complex aetiology involving both environmental and genetic risk factors. Although some of the major risk factors for stoke, such as smoking and hypertension, are welldocumented, the underlying genetic and detailed molecular mechanisms remain elusive. Exploring the relevant biochemical pathways may contribute to the clinical diagnosis of stroke and shed light on its aetiology. Methods: A comparative proteomic analysis of blood serum of a pair of monozygotic (MZ) twins discordant for ischaemic stroke (IS) was performed using a label-free quantitative proteomics approach. To overcome the limit of reproducibility in the serum preparation, two separate runs were performed, each consisting of three technical replicates per sample. Biological processes associated with proteins differentially expressed between the twins were explored with Gene Ontology (GO) classification using the functional analysis tool g:Profiler. Results: ANOVA test performed in Progenesis LC-MS identified 179 (run 1) and 209 (run 2) proteins as differentially expressed between the affected and unaffected twin (P<0.05). Furthermore, the level of serum fibulin 1, an extracellular matrix protein associated with arterial stiffness, was on average 13.37-fold higher in the affected twin. Each dataset was then analysed independently, and the proteins were classified according to GO terms. The categories overrepresented in the affected twin predominantly corresponded to stroke-relevant processes, including wound healing, blood coagulation and haemostasis, with a high proportion of the proteins overexpressed in the affected twin associated with these terms. By contrast, in the unaffected twin diagnosed with atopic dermatitis, there were increased levels of keratin proteins and GO terms associated with skin development. 3 Conclusion: The identification of cellular pathways enriched in IS as well as the up-regulation of fibulin 1 sheds new light on the underlying disease-causing mechanisms at the molecular level. Our findings of distinct proteomic signatures associated with IS and atopic dermatitis suggest proteomic profiling could be used as a general approach for improved diagnostic, prognostic and therapeutic strategies.

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Section: Discussionmentioning

confidence: 99%

Distinct proteomic profiles in monozygotic twins discordant for ischaemic stroke

et al. 2019

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“…Under normal condition, the expression of MMPs in the brain is very low. Ischemic stroke may induce increased expression of MMPs, especially MMP9 . Both brain vascular ECs and infiltrating neutrophils can produce MMP9 after focal cerebral ischemia, which can be used to predict stroke patient outcome .…”

Section: The Double‐faced Roles Of Peripheral Immune Activation On Thmentioning

confidence: 99%

“…Ischemic stroke may induce increased expression of MMPs, especially MMP9 . Both brain vascular ECs and infiltrating neutrophils can produce MMP9 after focal cerebral ischemia, which can be used to predict stroke patient outcome . In ischemic stroke patients, MMP9 increases in the plasma within the first 2 to 6 hours and the MMP9 mRNA in leukocytes increased within 3 hours Activated neutrophils may be an important source of pre‐existing intracellular MMP9 pool, which can be secreted in response to middle cerebral artery occlusion (MCAO) and oxygen‐glucose deprivation (OGD) insults In addition, activated MMPs may also be triggered by increased TNF‐ α, IL‐6, and α2‐antiplasmin in the blood The granulocyte‐colony stimulating factor (G‐CSF) can stimulate the proliferation of peripheral neutrophils and thus increase the level of MMP9, leading to exacerbated BBB disruption and increased ischemic infarction …”

Section: The Double‐faced Roles Of Peripheral Immune Activation On Thmentioning

confidence: 99%

The peripheral immune response after stroke—A double edge sword for blood‐brain barrier integrity

Zhu

Huang

et al. 2018

CNS Neurosci Ther

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Summary The blood‐brain barrier (BBB) is a highly regulated interface that separates the peripheral circulation and the brain. It plays a vital role in regulating the trafficking of solutes, fluid, and cells at the blood‐brain interface and maintaining the homeostasis of brain microenvironment for normal neuronal activity. Growing evidence has led to the realization that ischemic stroke elicits profound immune responses in the circulation and the activation of multiple subsets of immune cells, which in turn affect both the early disruption and the later repair of the BBB after stroke. Distinct phenotypes or subsets of peripheral immune cells along with diverse intracellular mechanisms contribute to the dynamic changes of BBB integrity after stroke. This review focuses on the interaction between the peripheral immune cells and the BBB after ischemic stroke. Understanding their reciprocal interaction may generate new directions for stroke research and may also drive the innovation of easy accessible immune modulatory treatment strategies targeting BBB in the pursuit of better stroke recovery.

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“…The latest guideline of acute stroke treatment still recommends tPA as the first‐line of effective thrombolytic treatment to achieve early reperfusion of the ischemic brain . However, the current therapeutic window of 4.5 hours after the onset of stroke remarkably limits the clinical use of tPA thrombolysis . BBB disruption is a fundamental pathological feature of intracerebral HT induced by tPA thrombolysis .…”

Section: Discussionmentioning

confidence: 99%

“…2,3,30 However, the current therapeutic window of 4.5 hours after the onset of stroke remarkably limits the clinical use of tPA thrombolysis. [31][32][33] BBB disruption is a fundamental pathological feature of intracerebral HT induced by tPA thrombolysis. 34,35 Loss of BBB integrity results in increased vascular permeability and is associated with reduced cerebral blood flow and impaired hemodynamic responses.…”

Section: Discussionmentioning

confidence: 99%

Rosiglitazone ameliorates tissue plasminogen activator‐induced brain hemorrhage after stroke

Zhu

et al. 2019

CNS Neurosci Ther

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Objective Delayed thrombolytic therapy with recombinant tissue plasminogen activator (tPA) may exacerbate blood‐brain barrier (BBB) breakdown after ischemic stroke and lead to catastrophic hemorrhagic transformation (HT). Rosiglitazone(RSG), a widely used antidiabetic drug that activates peroxisome proliferator‐activated receptor‐γ (PPAR‐γ), has been shown to protect against cerebral ischemia through promoting poststroke microglial polarization toward the beneficial anti‐inflammatory phenotype. However, whether RSG can alleviate HT after delayed tPA treatment remains unknown. In this study, we sort to examine the role of RSG on tPA‐induced HT after stroke. Methods and results We used the murine suture middle cerebral artery occlusion (MCAO) models of stroke followed by delayed administration of tPA (10 mg/kg, 2 hours after suture occlusion) to investigate the therapeutic potential of RSG against tPA‐induced HT. When RSG(6 mg/kg) was intraperitoneally administered 1 hour before MCAO in tPA‐treated MCAO mice, HT in the ischemic territory was significantly attenuated 1 day after stroke. In the tPA‐treated MCAO mice, we found RSG significantly mitigated BBB disruption and hemorrhage development compared to tPA‐alone‐treated stroke mice. Using flow cytometry and immunostaining, we confirmed that the expression of CD206 was significantly upregulated while the expression of iNOS was down‐regulated in microglia of the RSG‐treated mice. We further found that the expression of Arg‐1 was also upregulated in those tPA and RSG‐treated stroke mice and the protection against tPA‐induced HT and BBB disruption in these mice were abolished in the presence of PPAR‐γ antagonist GW9662 (4 mg/kg, 1 hour before dMCAO through intraperitoneal injection). Conclusions RSG treatment protects against BBB damage and ameliorates HT in delayed tPA‐treated stroke mice by activating PPAR‐γ and favoring microglial polarization toward anti‐inflammatory phenotype.

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Inflammatory and metalloproteinases profiles predict three-month poor outcomes in ischemic stroke treated with thrombolysis

Cited by 38 publications

References 33 publications

Distinct proteomic profiles in monozygotic twins discordant for ischaemic stroke

Distinct proteomic profiles in monozygotic twins discordant for ischaemic stroke

The peripheral immune response after stroke—A double edge sword for blood‐brain barrier integrity

Rosiglitazone ameliorates tissue plasminogen activator‐induced brain hemorrhage after stroke

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